Preparation of unsaturated compounds of the cyclopentanopolyhydrophenanthrene series



PREPARATION OF UNSATURATED COMPOUNDS OF THE CYCLOPENTANOPOLYHYDROPHEN'ANTI-IRENE SERIES Willem Jacob van der Burg, Oss, Netherlands, assignorto Organon Inc., Orange, N.J., a corporation of New Jersey;

No Drawing. Application September 24, 1957 Serial No. 685,828

Claims priority, application Netherlands October 23, 1956 Claims. (Cl.260-3973) The invention relates to a process for the preparation ofunsaturated compounds of the cyclopentanopolyhydrophenanthrene serieswhich have one or more double bonds in a-position relatively to a ketogroup and ing agent is applied for each double bond which has. to beintroduced. I

The starting substances may have any steric configuration and may alsooccur as racemates; as examples are mentioned the 3-ketones of thecompounds of the cholestane, spirostane, furostane, cholane, norcholane,bisnorcholane, pregnane, or androstane series. Also the 3-keto-18 and19-nor compounds, as well as the 18,19- bisnor compounds and also theC-nor and D-homo steroids may be used as starting products. They may 1be saturated or contain double bonds e.g. in the positions especially tothe preparation of 3-keto compounds of this, series which have a doublebond in the positions 1-2 and/ or 4-5, and of functional derivativesthereof. These compounds are of great importance, because in addition toadrenocortical hormones, they also comprise other substances with greatbiological activity, such e.g. as 1- dehydrohydrocortisone,l-dehydrocortisone, l-dehydroaldosterone, and their 2-alkyl and/or 9 and12 halogen derivatives, and valuable intermediate products, such e.g. asA andrQstadiene-S-one-17-one or 17-01.

The present invention relates to a process for the preparation ofdehydro compounds of the cyclopentanopolyhydrophenanthrene series and ischaracterized, in that into a keto compound of this series, saturated inat least one of the u-positions relatively to the keto group, at leastone double bond is introduced in a-position relatively to the said ketogroup by treatment with an iodine compound chosen from the groupconsisting of periodic acid, iodic acid, iodine pentoxide and compoundscapable of supplying these compounds during the reaction.

According to the process of the present invention there can be preparede.g. A -3-keto compounds, A -5a-3-keto compounds, A -3-keto compounds,and A -3-keto compounds. The A -3-keto compounds are formed from the513-3-ketones which are saturated in ring A, the A -Sa-B-keto compoundsfrom the saturated Sa-S-ketones, while for the preparation of A -3rketocompounds both the saturated 5,9 and 5a-3-ketones and also the A and theA -3-ketones may be used.

Starting with 3-keto steroids entirely saturated in ring A, the presentdehydrogenation reaction may yield, in addition to the desireddehydrogenation products, such as the A A and A -3-keto steroids, asby-products the 2-iodine and 4-iodine compounds, of 3-keto-5u and3-keto-5fl steroids. In order to obtain a better yield of the desiredunsaturated compounds, it is of advantage to treat these 2-iodine or4-iodine compounds, if desired after isolation from the reaction medium,with hydrazine or a derivative thereof, such as phenylhydrazine,dinitrophenylhydrazine and semicarbazide, after which the formed productcan be converted into the corresponding A or A B-keto steroids by acidhydrolysis or by an exchange reaction with a ketone, such as pyruvicacid, or with an aldehyde, such as benzaldehyde, hydroxybenzaldehyde andcarboxybenzaldehyde,

The quantity of dehydrogenating agent which is used for the presentreaction is, dependent on the starting product, on the nature of thedehydrogenating agent, and on the reaction conditions, such as solventand temperature at which the reaction is carried out. In general it mabe said that at least one equivalent of dehydrogenat- 1 or 4, and alsoin the positions 5, 6, 7, 8, 9:11, 11, 14, 16 or 17, and contain furthersubstituents, such as free or functionally converted oxy, oxo,oxymethyl, formyl, carboxyl, or oxalyl groups, alkyl, e.g. methylgroups, epoxy groups, or halogen atoms, e.g. in the positions 2, 4, 5',6, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18', 19, 20 or 21.

Especially important starting substances are progesterone,ll-dehydroprogesterone, 11, 12, 14, 15', 16, 17, 18 orl9-oxy-progesterone, ll-desoxycorticosterone, cortisome, hydrocortisone,ll-epihydrocortisone, aldosterone, 18-oxycorticosterone,1l-epi-l8-oxy-corticosterone, 17ozoxy-aldosterone,18-oxy-hydrocortisone, 18-oxy and 18- oxocortisone, 18-oxy and'18-oxocortexone, 17a-oxycortexone, 17a,l8-dioxycortexone, correspondingcompounds which, instead of in 4-position, are unsaturated in l-positionor in the positions 4 and 6, e.g.:

A 4 17 a,21 -dihydroxy-.3,l 1,ZO-triketo-pregnadiene;

A -1 1,9,21-dihydroxya3,ZO-diKeto-pregnadiene;

M' -1 15,21-dihydroxy-3,ZO-diketo-pregnadiene-18-a1;

A -1 10,21 -dihydroxy-3 ,2O-diketo-pregnadiene;

A 115,17u,2l 7 trihydroxy 9a fiuoro 3,20 diketopregnadiene;

A llfi,l7a,2l trihydroxy 9a chloro 3,20 diketopregnadiene;

A 1lfi,17oc,21 trihydroxy 9abromo 3,20 -.diketopregnadiene; 1

A 2 methyl 11;3,l7ci.,21 trihydroxy 3,20 diketopregnadiene;

A 2 methyl 11fi,l7a,21 trihydroxy 9 halo,-

3,ZO-diketo-pregnadiene;

A 3,20 diketo w fluoro 115,21 dioxy pregnadiene and functional.derivatives of any of the aforesaid compounds.

If as starting product a compound is applied which contains several ketogroups, it may be necessary to temporarily block a keto group inducingthe introduction of a non-desired double bond in a-position.

If use is made of periodic acid it may be desirable, in case thestarting substances are u-diols or u-ketols, to protect at least one ofthe two groups. A hydroxyl group is protected e.g., by esterification, aketo group e.g. by ketalization.

In the starting substances the hydroxyl groups may be functionallyconverted, i.e. may be esterified, e.g. with an aliphatic, aromatic, orheterocyclic carboxylic acid, e.g. acetic acid, trimethyl acetic acid,benzoic acid, or furane carboxylic acid, or may be etherified, e.g. tothe tetrahydropyranyloxy, benzyloxy, or triphenylmethoxy groups.Functionally converted keto groups are preferably ketalized geto groups,e.g. derived from a bivalent alcohol, such as the ethylene dioxidegroups.

The used dehydrogenating agents, periodic acid, iodic acid and iodinepentoxide, may be applied as such or in the form of afunctional-derivative, e.g. a salt. In the latter case it is necessary,in order to liberate the iodic or periodic acid, to add. to the reactionmixture a strongly dissociated acid, e.g. a mineral acid. In addition tothe said salts of iodic acid and periodic acid, such as po- 1' a earnetas'sium iodate and sodium periodate, there are still other compoundswhich, in a suitable reaction medium, can

. supply iodic acid and canfconsequently be applied as dehydrogenatingagents; As examples thereof are mentioned the iodic oxides I and I 0 andthe salts of inorganic and organic acids, in which iodine occurs astrivalent cation, such as IP0 I(JO I (N0 and The dehydrogenationaccording to the present process ispreferably carried out in an aqueousor non-aqueous polar organic solvent or in a mixture of a polar and anan-polar solvent. Preferably the reaction is carried out in thepresence of an aliphatic carboxylic acid such as acetic acid andpropionic acid or of ,a tertiary alcohol,

such as tertiary butanol and tertiary amyl alcohol or of aN,N'-dialkylacylamide e.g. dimethyl formamide. Also thefollowingsolvents, especially mixed with the said alcohols, may be used: dioxane,glacial acetic acid, acetic organic or organic acid, preferably anorganic acid, such as acetic acid, propio'nic'acid. or benzoic acid. Theorganic acid, e.g. acetic acid, or propionic acid, may in some cases atthe same time serve as a solvent for the reaction components.

Any excess of dehydrogenating agent can be removed e.g. by washing outwith water or by reduction with sodium sulphite, sodium .bisulphite, andthe like, followed by washing. out. v

The purification of the reaction products can e.g. be carried out bychromatography, e.g. over aluminum oxide or silica gel, by distributionmethods, e.g. according to the counter current method, or by separationby means of a Girard reagent, such as trimethyl amino acetic hydrazideor pyridine acetic acid hydrazide. Furtherto the purification or insteadof it the products may be recrystallized from organic or aqueous organicsolvents.

The reaction products, obtained according to the process may beconverted into'their functional derivatives by methods known per se,e.g. esters, ethers, enolesters, enolethers, ketals, thioethers andthioketals, and also hydrazones, oximes and enamines. In these compoundsthe hydroxyl and/or keto groups may be completely or partiallyfunctionally converted.

' The following'examples illustrate the invention.

' Example I To a solution of 0.6 g. of A -l7a,2l-dihydroxy-3,1l,20-triketopregnene-2l-acetate in 30 ml. of tert. butanol and 2'ml. ofglacial acetic acid 1.2 g. of periodic acid are added. Boiling iscarried out under reflux for 30 minutes. Subsequently the reactionmixture is diluted with 30 ml. of water and 3 g. of sodium sulphite areadded. The tert. butanol is removed in vacuo. Then extraction is carriedout with chloroform. The combined extracts are washed with water, driedon Na S0 This extract is evaporated to dryness under reduced pressureand the residue is taken up in acetone. It yields crystals of the A170:21 dihydroxy 3,11,20 triketo pregnadiene- 21-acetate melting at228233 C., (a) =+190 (dioxane).

Example II To a solution of 0.6 g. of A -1lip,17a,21-trihydroxy3,20-dikctopregnene-2l-acetate in 32 ml. of dioxane are added 2.5 g. ofbenzoic acid and 1.2 g. of periodic acid. After boiling under nitrogenfor 30 minutes the reaction mixture is processed as described in ExampleI. Obtained is the A-l1B,l741-2l-trihydroxy-3,20-diketopregnadiene-Zl-acetate.

Example III 1 g. of A -3,17-diketo-androstene is added to a mix- 4 tureof 40 ml. of tert. butanol and 2 ml. of dimethyl formamide. Whilestirring the mixture is heated to 50 C. and 400 mg. of periodic acid areadded. Then another 4 times 400 mg. of HIO .2H O are added withintervals of 1 hour. Finally the reaction mixture is stirred at 50 C.for another 24 hours, then poured into a solution of 6 g. of sodiumsulphite in 50 ml. of water. The tert. butanol is distilled off in vacuoand the aqueous residue is extracted with ether. The combined extractsare washed with water, dried on sodium sulphate, and evaporated todryness in vacuo. 2 ml. of quinoline are added to the remainingcolourless oil and the mixture is heated on a water-bath for 15 minutes.After cooling the molecular compound of A -3,17-diketo-androstadienecrystallizes out with quinoline. This is sucked oh and washed withlittle ether. The resulting molecular compound is suspended in 20 ml. ofether and this suspension is shaken with 20 ml. of 2 N sulphuric acid.The aqueous layer is then removed and the ether layer is washed withwater till neutral, dried on sodium sulphate and evaporated to a smallvolume (2 or 3 ml.). The resulting A -3,17-diketo androstadiene iscolourless and melts at 139-140 C.

added and stirred at 70 for 15 hours.

Example IV 1 g. of 3,17-diketoandrostane is added to 50 ml. oftert.butanol and the mixture is heated at 70 C. while stirring. Then 1.2 g.of potassium periodate in finely powdered form and 0.8 ml. ofconcentrated hydrochloricacid are After cooling the mixture is pouredinto a solution of 2 g. of Na SO in 50 ml. of water. Then the greaterpart of the tert. butanol is removed by evaporation in vacuo. Theresulting cloudy 0.6 g. of 17a,21-dihydroxy-3,11,20-triketoallopregnaue-21-acetate (m.p. 227-229") is added to 40 ml. of tert. amylalcohol and 2ml. of glacial acetic acid. 250 mg. of periodic acid are added afterwhich the mixture is heated to 70". Then another 4 times 250 mg. ofperiodic acid are added with intervals of 30 minutes, after which themixture is heated at 70 for another 20 hours. The reaction mixture isprocessed as described in Example I. Obtained is the A*-17e,21-dihydroxy-3,l1,20-triketopregnadiene-2l-acetate melting at228232.

Example V1 0.3 g. of A-7a,21-dihydroxy-3,l1,20-triketo-allo-pregnene-Zl-acetate and 0.9 g. ofperiodic acid are added to 15 ml. of tort. amylalcohol. 2.5 ml. ofglacial acetic acid are added, after which the mixture is boiled underreflux for 3% hours. After processing the reaction mixture it appearsfrom the paper chromatogram that mainly A :,21 dihydroxy 3,11,20 triketopregnadiene- 2l-acetate has formed.

Example VII 0.1 g. of M' -3,l7-diketo-androstadiene is stirred at 70' C.for 16 hours with 0.5 ml. of concentrated hydrochloric acid and 200 mg.of sodium periodate and 10 ml. of tort. butanol. The process of thereaction mixture is carried out as described in Example I. Obtained are60 mg. of (3 3,17-diketo-androstatriene. M.p. 166 C.; +72".

- Example VIII A mixture of 0.5 g. of A--1lfl,17a,21-trihydroxy.-3,20-

. 5 diketopregnadiene-Zleacetate and 900mg. of periodieacid in 30 ml. oftert. butanol is stirred at 75 C. for 15 hours. The resulting reactionmixture is processed as described in Example I. Obtained is the A-11p,17e,21-trihydroxy-3,20-diketopregnatriene-2l-acetate. In the samemanner the A -17a, 2l-dihydroxy-9-halo-3,11,20-triketo-pregnatrienes andthe, A -11B,17a,21-trihydroxy- 9a-halo-3,20-diketo-pregnatrienes can beprepared starting from the corresponding A -3,ketones.

Example IX 0.3 g. of A-9a-fluoro-1l5,17a,21-trihydroxy-3,20,diketopregnene-Zl-acetate isdissolved in 15 ml. of tert. butanol and 1 ml. of propionic acid. Addedis 0.7 g. of periodic acid, after which the mixture is kept at 80 for 20hours (under nitrogen). The process is carried out as described inExample I. Obtained is the A -9a-fll10lO-11B,17o:,21-trihydroxy-3,ZO-diketopregnadiene-Zl-acetate, m.p. 239 C.

Example X 1.5 g. of iodine pentoxide are added to a solution of 1 g. ofA -l7a,21-dihydroxy-3,11,ZO-triketopregnene-Zl-acetate in 5 ml. ofglacial acetic acid. The mixture is stirred at 70 C. for 8 hours.Subsequently the reaction mixture is diluted with 80 ml. of water andextracted with chloroform. The extract coloured purple by iodine isshaken with a dilute solution of sodium sulphite in water until thepurple colour has disappeared, then washed with ice cold 1 N sodiumhydroxide solution, and finally with Water till neutral. After drying onanhydrous sodium sulphate the extract is evaporated to dryness.Crystallization from acetone yields the A-17a,21-dihydroxy-3,11,20-triketopregnadiene-Zl-acetate melting at229233 C. ((1) +190 (dioxane).

Example XI 0.6 g. of A -11fl,17a,21-trihydroxy-3-,20-diketopregnene-21-acetate is brought into a mixture of 30 m1. of tetrahydrofurane and 5ml. of propionic acid. 1 g. of I and two drops of water are added. Afterstirring for 48 hours at 50 C. the reaction mixture is processed asdescribed in Example X. Crystallization from acetone yields the21-acetate of A -1 1 8,17u,21-trihydroxy-3,20- I diketo-pregnadienemelting at 237 C.

Example XII Example XIII 1 g. of 3,17-diketo-androstane is brought into10 ml. of tertiary amyl alcohol and the mixture is heated to 70 C. whilestirring. Then 1.2 g. of sodium iodate in a powdered form and 0.9 ml. ofconcentrated hydrochloric acid are added and stirred at 70 C. for 17hours.

After cooling the mixture is poured into a solution of 2 g. of sodiumsulphite in 50 ml. of water. The tertiary amyl alcohol is removed forthe greater part by evaporating in vacuo. The resulting liquid isextracted a few times with ether. The collected extracts aresubsequently washed with water and then dried on sodium sulphate. Theethereal solution is evaporated to 15 ml., after which herefrom the A-3,17-diketo-androstene with meltingpoint 137-138" C. is obtained.

Paper chromatographically the A -3,l7-diketo-androstadiene and the A-3,17 diketo-androstene have been demonstrated in the mother-liquor ofthe crystallisate.

Example XIV 2 g. of 17a,21-dihydroxy-3,11,20-triketo-pregnane-21-acetate and 1.5 g. of iodine iodate (I(IO are brought .into 5 ml. oftertiary butanol. The mixture is stirred at a temperature of 70 C. for15 'm'iiiutsj Them-in aperiod of 20 minutes, a mixture of 1 ml. of waterand 5 ml.- of

tertiary butanol is added dropwise. Then heating at 70 C. is continuedfor another 6 hours. The cooled reaction mixture is processed asdescribed in Example XIII.

Obtained is the A -17ot,2l-dihydroxy-3,L1,20-triketo''pregnene-21-acetate with a melting-point of 238'-240 C.

Example XV 0.6 g. of 11,6,17a,21-trihydroxy-3,ZO-diKeto-pregnane-21-acetate and 1 g. of iodic acid are brought into 6 ml. of acetic acid.The mixture is heated at 65 C. for 15 hours. The product isolated fromthe reaction mixture is recrystallized from acetone. Obtained is the A17a,21-trihydroxy-3,20-diketo-pregnadiene-2l-acetate with amelting-point of 236237 C.

Example XVI 1 g. of 17a,21-dihydroxy-3, ll, 20-triketo-pregnane-21-acetate is brought into 10' ml. of tertiary butanol. Then 1.5 g. ofiodine triacetate and 0.5 ml. of water are added. The mixture is stirredat a temperature of 70 C. for 15 hours and then processed, as describedin Example XIII, in which the A-l7a,21-dihydroxy-3,11,20-triketo-pregnene-ZI-acetate with amelting-point of 23824l C. is obtained.

' Example XVII A suspension of 0.5 g. of A '-17a,21-dihydroxy-3,11,20-triketo-pregnadiene-Zl-acetate and 1 g. of iodine pentoxide in a mixtureof 5 ml. of tertiary amyl alcohol and 5 ml. of glacial acetic acid areheated, while stirring, at 70 C. under nitrogen for 15 hours. Theprocess of the reaction mixture is carried out as described in ExampleX.

Obtained is the A-l7a,21-dihydroxy-3,11,20-triketopregnatriene-Zbacetate with amelting-point of 223- 225 C.

Example XVIII 0.3 g. of A-17u,21-dihydroxy-3,11,2O-triketo-allopregnene-21-acetate and 0.5 g. ofiodic. acid are brought into 10 ml. of tertiary butanol. To this isadded 0.2 ml. of water, after which the mixture is heated, whilestirring, at 70 C. for 15 hours. After processing the reaction mixture,as described in Example X, the A-17a,21-dihydroxy-3,11,20-triketo-pregnadiene-2l-acetate is obtained.

Example XIX A mixture of 0.5 g. of M' -11 8,17a,21-trihydroxy-3,20-diketo-pregnadiene-2l-acetate and 900 mg. of iodic acid in 10 ml. oftertiary butanol are stirred at 75 C. for 20 hours. The reaction mixtureis processed as described in Example X. Obtained is the A-11B,17a,21-trihydroxy- 3,ZO-diketo-pregnatriene-2l-acetate. In the samemanner, starting from the corresponding A -3-ketones, are prepared the A-17a,21dihydroxy-9-halo-3,11,20-triketopregnatrienes and the A1546 113,l7a,21 trihydroxy 9oz hale-3,ZO-diketo-pregatrienes.

Example XX 0.5 g. of 17a,21-dihydroxy-3,11,20-triketo-allopregnane-2l-acetate (melting-point 227-229") is brought into 5 ml. of glacialacetic acid. Added is 0.8 g. of iodic acid. The mixture is stirredintensively at a temperature of 70 C. for 18 hours. After cooling thereaction mixture is poured into water and further processed as describedin Example X.

Obtained is the A-17a,21-dihydroxy-3,11,20-triketopregnadiene-Zl-acetate melting at228-232 C.

I claim:

1. A process which comprises reacting a 3-keto compound selected fromthe group consisting of steroids of androstane and pregnane series,which compound is saturated in at least one of the positions l-2 and4-5, with a compound selected from the group consisting of periodic acidand iodic'ac id to efiect the introduction of at least one double bondin q-position relative to said 3-keto group.

2; Process according to claim 1, in which-the reaction is carried out inthe presence of an acid.

3. Process according to claim 1, in which the reaction is carried out ina solvent chosen from the group consistin; of a lower tertiary alcohol,a lower aliphatic carboxylic acid and a N,N'-di-lowcr alkyl acyiamide.

4. Process according to claim 3, i n which tert-hutanoi No referencescited.

1. A PROCESS WHICH COMPRISES REACTING A 3-KETO COMPOUND SELECTED FROMTHE GROUP CONSISTING OF STEROIDS OF ANDROSTANE AND PREGNANE SERIES,WHICH COMPOUND IS SATURATED IN AT LEAST ONE OF THE POSITIONS 1-2 AND4-5, WITH A COMPOUND SELECTED FROM THE GROUP CONSISTING OF PERIODIC ACIDAND IODIC ACID TO EFFECT THE INTRODUCTION OF AT LEAST ONE DOUBLE BOND INA-POSITION RELATIVE TO SAID 3-KETO GROUP.